The goal of this project is to improve the therapeutic index of intrathecal methotrexate for the treatment of brain tumors, meningeal leukemia, and other neoplasms primary or metastatic to the central nervous system. The approaches that will be taken include: 1) correlation of cerebrospinal-fluid antifolate concentrations with therapeutic and toxic effects, (2) identification of patient characteristics that influence the central-nervous-system pharmacokinetics of methotrexate, (3) Phase 2 and Phase 3 trials of intrathecal aminopterin, (4) pharmacological evaluation of the hyperbaric injection technic, (5) additional clinical experience with intraventricular chemotherapy via the Ommaya reservoir, and (6) the testing of new methods of central-nervous-system chemotherapy in murine and primate models. The latter will include evaluation of a variety of conditions on cerebrospinal-fluid methotrexate concentration: intravenous infusions of high-dose methotrexate, cranial irradiation, systemic and intrathecal probenicid administration, hyperbaric (D10W-Trendelenburg) intralumbar chemotherapy. A special effort will be made to develop a primate model of methotrexate-induced leukoencephalopathy and to determine what factors contribute to, prevent or reverse the toxicity. The ultimate objective is to eliminate the need for intrathecal methotrexate. This possibility will be explored by infusing very high doses (e.g., 22 Gm/sq.m of methotrexate intravenously for 24-42 hour periods, followed by citrovorum rescue. A prospective randomized trial is planned in patients scheduled to receive treatment for prevention of CNS leukemia.